Benzoheterocycle substituted tetrahydroisoquinoline compound

Abstract

The present invention provides a benzoheterocycle substituted tetrahydroisoquinoline compound, and in particular, relates to a compound shown in formula (I) and a pharmaceutically acceptable salt thereof, and the compound for the treatment of chronic kidney disease.

1 . A compound as shown in formula (I), an optical isomer thereof and a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein, 
         R 1  is selected from H, C 1-6  alkyl, C 3-6  cycloalkyl and 4-6 membered heterocycloalkyl, and the C 1-6  alkyl, C 3-6  cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R; 
         R 2 , R 3 , R 4 , R 5 , R 6  are each independently selected from H, halogen, OH, NH 2 , CN, C 1-6  alkyl and C 1-6  heteroalkyl, and the C 1-6  alkyl or C 1-6  heteroalkyl is optionally substituted with 1, 2 or 3 R; 
         R 7 , R 8  are each independently selected from H; 
         or, R 7  and R 1  are attached to form a 5-6 membered ring; 
         or, R 8  and R 1  are attached to form a 5-6 membered ring; 
         T is selected from N and CH; 
         ring A is selected from 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl, and the 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl is optionally substituted with 1, 2 or 3 R; 
         n is selected from 2 and 3; 
         L 1  is selected from 
       
       
         
           
           
               
               
           
         
          and the 
       
       
         
           
           
               
               
           
         
          is optionally substituted with 1, 2 or 3 R; 
         L 2  is selected from 
       
       
         
           
           
               
               
           
         
          and the 
       
       
         
           
           
               
               
           
         
          is optionally substituted with 1, 2 or 3 R; 
         L 3  is selected from a single bond, 
       
       
         
           
           
               
               
           
         
          and the 
       
       
         
           
           
               
               
           
         
          is optionally substituted with 1, 2 or 3 R; 
         L 4  is selected from 
       
       
         
           
           
               
               
           
         
          and the 
       
       
         
           
           
               
               
           
         
          is optionally substituted with 1, 2 or 3 R; 
         X is selected from a single bond, O, N, NH, C 3-10  cycloalkyl, 5-10 membered heterocycloalkyl, C 1-6  alkyl, C 5-10  aryl and 5-12 membered heteroaryl, and the C 3-10  cycloalkyl, 5-10 membered heterocycloalkyl, C 1-6  alkyl, C 5-10  aryl or 5-12 membered heteroaryl is optionally substituted with 1, 2 or 3 R X ; 
         R X  is each independently selected from OH, NH 2 , C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylthio, C 1-6  alkylamino, 5-6 membered heterocycloalkyl, —NHC(═O)N(C 1-6  alkyl) 2 , —NHC(═O)NHC 1-6  alkyl and —NHC(═O)C 1-6  alkyl-O—C 1-6  alkyl, and the C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylthio, C 1-6  alkylamino, 5-6 membered heterocycloalkyl, —NHC(═O)N(C 1-6  alkyl) 2 , —NHC(═O)NHC 1-6  alkyl or —NHC(═O)C 1-6  alkyl-O—C 1-3  alkyl is optionally substituted with 1, 2, 3, 4 or 5 R; 
         R is each independently selected from H, halogen, OH, NH 2 , CN, 
       
       
         
           
           
               
               
           
         
          C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylthio, C 1-6  alkylamino and 5-6 membered heterocycloalkyl, and the NH 2 , C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylthio, C 1-6  alkylamino or 5-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R′; 
         R′ is selected from F, Cl, Br, I, OH, NH 2 , CH 3  and COOH; 
         the 4-6 membered heterocycloalkyl, C 1-6  heteroalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, 5-6 membered heteroaryl, 6-12 membered heteroaromatic ring and 5-10 membered heterocyclyloalkyl contains 1, 2 or 3 heteroatoms or heteroatomic groups independently selected from 0, NH, S, C(═O), C(═O)O, S(═O), S(═O) 2  and N. 
       
     
     
         2 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 1 , wherein, R is selected from H, F, Cl, Br, I, OH, NH 2 , COOH, 
       
         
           
           
               
               
           
         
         Me, CF 3 , 
       
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 1 , wherein, R 1  is selected from H, CH 3 , 
       
         
           
           
               
               
           
         
          piperidinyl and tetrahydropyrrolyl, and the CH 3 , 
       
       
         
           
           
               
               
           
         
          piperidinyl or tetrahydropyrrolyl is optionally substituted with 1, 2 or 3 R. 
       
     
     
         4 . The compound according to  claim 3 , the optical isomer thereof and the pharmaceutically acceptable salt thereof, wherein, R 1  is selected from H, CH 3 , 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 1 , wherein, R 2 , R 3 , R 4 , R 5 , R 6  are independently selected from H, F, Cl, Br, OH, NH 2 , CN, CH 3 , 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 1 , wherein, ring A is selected from pyrrolidin-2-one group, isothiazolidine-1,1-dioxide group, 1,2-thiazine-1,1-dioxide group, piperidin-2-one group, 3,4-dihydropyridin-2(1H)-one group, 5,6-dihydro-2H-1,2-thiazine-1,1-dioxide group, pyridinyl group and pyrazolyl group, and the pyrrolidin-2-one group, isothiazolidine-1,1-dioxide group, 1,2-thiazine-1,1-dioxide group, piperidin-2-one group, 3,4-dihydropyridin-2(1H)-one group, 5,6-dihydro-2H-1,2-thiazine-1,1-dioxide group, pyridinyl group or pyrazolyl group is optionally substituted with 1, 2 or 3 R. 
     
     
         7 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 6 , wherein, the structural moiety 
       
         
           
           
               
               
           
         
         is selected from 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         8 . The compound, the optical isomer thereof, and the pharmaceutically acceptable salt thereof according to  claim 1 , wherein, L 1  is selected from 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound, the optical isomer thereof, and the pharmaceutically acceptable salt thereof according to  claim 1 , wherein, L 2  is selected from 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound, the optical isomer thereof, and the pharmaceutically acceptable salt thereof according to  claim 1 , wherein, L 3  is selected from a single bond, 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound, the optical isomer thereof, and the pharmaceutically acceptable salt thereof according to  claim 1 , wherein, L 4  is selected from 
       
         
           
           
               
               
           
         
         the 
       
       
         
           
           
               
               
           
         
         is optionally substituted with 1, 2 or 3 R. 
       
     
     
         12 . The compound, the optical isomer thereof, and the pharmaceutically acceptable salt thereof according to  claim 11 , wherein, L 4  is selected from 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound, the optical isomer thereof, and the pharmaceutically acceptable salt thereof according to  claim 1 , wherein, the structural unit 
       
         
           
           
               
               
           
         
         is selected from 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . The compound, the optical isomer thereof, and the pharmaceutically acceptable salt thereof according to  claim 1 , wherein, X is selected from a single bond, N, NH, O, C 1-6  alkyl, C 3-8  cycloalkyl, 5-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl, and the C 1-6  alkyl, C 3-8  cycloalkyl, 5-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1, 2 or 3 R X . 
     
     
         15 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 1 , wherein, R X  is selected from OH, NH 2 , 
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound, the optical isomer thereof and the pharmaceutically acceptable salt thereof according to  claim 1 , wherein, X is selected from a single bond, N, NH, O, 
       
         
           
           
               
               
           
         
       
     
     
         17 . A compound represented by the following formula, an optical isomer thereof and a pharmaceutically acceptable salt thereof, selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         18 . A method for inhibiting NHE-mediated reverse transport of sodium or hydrogen ions in a subject in need thereof, comprising: administering the compound, the optical isomer thereof or the pharmaceutically acceptable salt thereof according to  claim 1  to the subject. 
     
     
         19 . A method for treating irritable bowel syndrome, heart failure, chronic kidney disease, end-stage renal disease or liver disease in a subject in need thereof, comprising: administering the compound, the optical isomer thereof or the pharmaceutically acceptable salt thereof according to  claim 1  to the subject.